Self-assembling nanoparticles composed of transmembrane peptides and their application for specific intra-tumor delivery of anti-cancer drugs
Inventors
Tarasova, Nadya I. • Tarasov, Sergey G. • Michejda, Christopher J.
Assignees
US Department of Health and Human Services
Publication Number
US-9326950-B2
Publication Date
2016-05-03
Expiration Date
2027-11-06
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Abstract
The invention provides a method of handling a hydrophobic agent, which method comprises (a) combining in an aqueous solution (i) a hydrophobic agent and (ii) an isolated peptide that is a structural analog of a transmembrane domain of an integral membrane protein, wherein one terminus of the peptide has one or more negatively charged residues, and (b) allowing the peptide to self-assemble into nanoparticles, wherein the nanoparticles comprise the hydrophobic agent.
Core Innovation
The invention provides a method of handling hydrophobic agents by combining in an aqueous solution a hydrophobic agent and an isolated peptide that is a structural analog of a transmembrane domain of an integral membrane protein, wherein one terminus of the peptide has one or more negatively charged residues, and then allowing the peptide to self-assemble into nanoparticles comprising the hydrophobic agent. The isolated peptides corresponding to transmembrane (TM) domains self-assemble into stable nanoparticles in aqueous solution, forming a unique delivery system.
The problem being solved relates to the limitations of liposomes as delivery systems for hydrophobic agents, such as anti-cancer drugs. Liposomes suffer from difficulties in industrial manufacture, lack of stability, and reproducibility, which hampers their wider use. There is a need for an alternative delivery system exhibiting advantages of liposomes but with superior stability, uniformity, ease of use, reproducibility, and smaller particle size.
The approach described involves TM peptides with at least about 10 amino acids structurally analogous to TM domains that include one terminus bearing negatively charged residues (preferably at the C-terminus). These peptides self-assemble, possibly by forming β-loop structures, into nanoparticles that encapsulate hydrophobic agents within their hydrophobic core. Addition of hydrophilic oligomers such as polyethylene glycol (PEG) to the same terminus containing the negative charges prevents aggregation and promotes formation of nanoparticles with uniform shape and size, suitably around 3 nm to 50 nm in diameter, preferably 8 nm to 20 nm. These nanoparticles can deliver hydrophobic agents effectively to tumors due to enhanced permeability and retention effects.
Claims Coverage
The patent contains one independent method claim and one independent composition claim, each focusing on nanoparticles comprising specific TM peptides and hydrophilic oligomers.
Method of preparing nanoparticles from CXCR4 transmembrane peptides with charged termini and PEG
A method that combines an aqueous solution with an isolated peptide consisting of about 20 to about 25 amino acids of a CXCR4 transmembrane domain having 2 or 3 consecutive negatively charged residues at the carboxyl terminus, adds a hydrophilic oligomer (PEG of 11 to 27 monomeric units) to that terminus, and allows the peptide to self-assemble into nanoparticles with uniform shape and diameter.
Composition of nanoparticles from CXCR4 transmembrane peptides with PEG hydrophilic oligomer
A composition comprising nanoparticles produced by combining the same isolated CXCR4 transmembrane peptide with 2 or 3 consecutive negatively charged residues at the carboxyl terminus, adding PEG with 11 to 27 monomeric units at that terminus, and allowing the peptide to self-assemble into uniformly shaped nanoparticles. The nanoparticles may have diameters from about 3 nm to 50 nm, preferably 8 nm to 20 nm, and peptides may comprise SEQ ID NO: 1. The composition can further include tumor-targeting ligands binding cell surface receptors overexpressed in tumor cells.
The independent claims cover methods and compositions of nanoparticles formed from CXCR4 transmembrane domain peptides with negatively charged carboxyl termini modified with PEG of specified length, which self-assemble into uniform nanoparticles suitable for delivery applications, particularly in targeting tumors.
Stated Advantages
The nanoparticles exhibit superior stability, uniformity, ease of use, and reproducibility compared to liposomes.
They have smaller particle size than liposomes, enabling better tumor penetration.
Nanoparticles have intrinsic biological activity, such as inhibiting cancer metastasis, angiogenesis, or drug resistance, providing dual activity when loaded with hydrophobic agents.
Addition of hydrophilic oligomers like PEG prevents nanoparticle aggregation, leading to uniform shape and size.
Nanoparticles enable effective delivery and concentration of hydrophobic anti-cancer agents in tumors due to enhanced permeability and retention effects.
Documented Applications
Delivery of hydrophobic agents, including anti-cancer drugs, to subjects, particularly for tumor targeting.
Chemotherapeutic treatment of cancer, including inhibiting tumor growth, invasiveness, metastasis, and promoting drug sensitivity by inhibiting drug resistance mechanisms.
Use in treating cancers such as lung, breast, prostate, head and neck, ovarian, skin, testicular, pancreatic, esophageal, colorectal, kidney, cervical, and gastrointestinal cancers.
Administration routes include intramuscular, transdermal, inhalation, topical, intratumoral, and parenteral methods.
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